Treatment of Allergic Rhinitis: H1-Antihistamines and Intranasal Steroids Pp-215-220
De-Yun Wang
Inflammation and Parkinson's Disease Pp-221-242
Christophe Wersinger and Anita
Sidhu
Peroxisome Proliferator-Activated Receptors
and the Control of Inflammation Pp-243-248
A. Cabrero, J.C. Laguna and M.
Vázquez
Chlamydial Heat Shock Protein 60 and
Lipopolysaccharide: Potential Virulence Determinants in Atherogenesis Pp-249-255
Murat V. Kalayoglu
The Mechanisms of Immune-to-Brain
Communication in Inflammation as a Drug Target Pp-257-262
Toru Hosoi, Yasunobu Okuma and
Yasuyuki Nomura
IL-4 and IL-13: Their Pathological Roles in
Allergic Diseases and their Potential in Developing New Therapies Pp-263-269
K. Izuhara, K. Arima and S.
Yasunaga
The Use of Leukotriene Modifying Drugs in
Asthma and Other Respiratory Diseases Pp-271-275
J.A. Corless and M. Paracha
A Role for Leptin in the Systemic
Inflammatory Response Syndrome (SIRS) and in Immune Response Pp-277-289
W. Waelput, P. Brouckaert, D. Broekaert and J. Tavernier
Oxidative Stress and Gene Transcription in
Asthma and Chronic Obstructive Pulmonary Disease: Antioxidant Therapeutic
Targets Pp-291-315
Irfan Rahman
[Back to top] Treatment of Allergic Rhinitis: H1-Antihistamines
and Intranasal Steroids
De-Yun Wang
Allergic rhinitis is charterized
as an inflammatory disease of the nasal mucosa.In clinical practice, H1-antihistamines and topical corticosteroids are most commonly used
pharmacological agents for the treatment of allergic rhinitis. The beneficial
effects of steroids depend upon their long-term anti-inflammatory effect rather
than upon direct receptor antagonism. This is different to H1--antihistamines,
which block both neural and vascular H1- receptors and have a clinical effect on
symptoms such as nasal itching,
sneezing, and rhinorrhea. H1--antihistamines are rapidly absorbed and
most of them are metabolized by the hepatic cytochrome P system and begin to
reduce nasal symptoms (itching and sneezing) within one hour. Understanding of
both the efficacy and the pharmacological properties of these commonly used
drugs in the treatment of nasal allergic inflammation and its related nasal
symptoms is very important. From a clinical viewpoint, it will provide a useful
guideline for an appropriate use of these drugs.
[Back to top] Inflammation and Parkinson's Disease
Christophe Wersinger and Anita
Sidhu
Numerous recent findings indicate
the possible involvement of an immune mechanism in the pathogenesis of neurodegeneration.
The immune reaction could either act as a primary event, generating changes
leading to cell death, or could be a secondary response to neuronal injury. In
various neurodegenerative disorders such as Alzheimer's, Huntington's or Pick's
disease, Down's syndrome, multiple sclerosis and the AIDS-dementia complex, the
inflammatory pathomechanism is strongly supported by experimental and clinical
studies. Such inflammatory mechanisms have also been postulated in Parkinson’s
disease (PD). This review summarizes some generalities about inflammation and
immune reactions in the context of the brain, and provides clinical,
epidemiological and experimental data showing that inflammation and immunity,
or even auto-immunity, could be implicated in PD, either in its initial step or
in its progression. Different experimental models useful for studying the
role(s) of inflammation and (auto)immunity in the neurodegenerative process of
the dopaminergic neurons in PD are examined. The major similarities and differences
between PD and other neurodegenerative disorders are discussed.
[Back to top] Peroxisome Proliferator-Activated Receptors and the
Control of Inflammation
A. Cabrero, J.C. Laguna and M. Vázquez
Peroxisome proliferator-activated
receptors (PPARs) are ligand-activated transcription factors which form a
subfamily of the nuclear receptor gene family. This subfamily consists of three
isotypes, a (NR1C1), g (NR1C3), and
b/d (NRC1C2) with a differential tissue
distribution. PPARa is expressed primarily in tissues with a high level of
fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal
muscle. PPARb is ubiquitously expressed, and PPARg has a restricted pattern of expression, mainly in white and brown
adipose tissues, whereas other tissues such as skeletal muscle and heart
contain limited amounts. Furthermore, PPARa
and g isotypes are expressed in vascular cells including endothelial and
smooth muscle cells and macrophages/foam cells. PPARs are activated by ligands,
such as naturally occurring fatty acids, which are activators of all three PPAR
isotypes. In addition to fatty acids, several synthetic compounds, such as
fibrates and thiazolidinediones, bind and activate PPARa and
PPARg,
respectively. In order to be transcriptionally active, PPARs need to
heterodimerize with the retinoid-X-receptor (RXR). Upon activation, PPAR-RXR
heterodimers bind to DNA specific sequences called peroxisome
proliferator-response elements (PPRE) and stimulate transcription of target
genes. PPARs play a critical role in lipid and glucose homeostasis, but lately
they have been implicated as regulators of inflammatory responses. The first
evidence of the involvement of PPARs in the control of inflammation came from
the PPARa null mice, which showed a prolonged inflammatory response.
PPARa
activation results in the repression of NF-kB signaling and inflammatory
cytokine production in different cell-types. A role for PPARg in inflammation
has also been reported in monocyte/macrophages, where ligands of this receptor
inhibited the activation of macrophages and the production of inflammatory
cytokines (TNFa, interleukin 6 and 1b), although part of the anti-inflammatory
effects of these ligands seems to be mediated by a mechanism not involving PPARg. All these findings suggest a role of PPARs in the control of the
inflammatory response with potential therapeutic applications in
inflammation-related diseases
[Back to top] Chlamydial Heat Shock
Protein 60 and Lipopolysaccharide: Potential Virulence Determinants in
Atherogenesis
Murat V. Kalayoglu
Chlamydia pneumoniae infection is
associated with atherosclerosis and may be an emerging risk factor in coronary
artery disease. C. pneumoniae can infect, multiply within and modulate the
function of all atheroma cell types. Specific chlamydial virulence determinants
have been identified that permit interaction with host cells and dysregulate
cell function. In particular, chlamydial heat shock protein 60 and
lipopolysaccharide may modulate cell function to dysregulate lipid metabolism,
induce inflammatory cytokine cascades and trigger production of cross-reactive
antibodies that initiate and promote atherogenesis. This paper reviews
chlamydial heat shock protein 60 and lipopolysaccharide as potential virulence
determinants in atherogenesis.
[Back to top] The
Mechanisms of Immune-to-Brain Communication in Inflammation as a Drug Target
Toru Hosoi, Yasunobu Okuma and
Yasuyuki Nomura
There is considerable evidence
that the peripheral immune system can signal the brain to elicit a sickness
response during infection and inflammation. The induction of the sickness
response involves the expression of proinflammatory cytokines such as
interleukin (IL)-1b, tumor necrosis factor-a
(TNF-a), and IL-6, both in the
periphery and in the brain. The mechanisms by which peripheral cytokines can
affect brain function have been the subject of much debate. The precise
mechanisms by which cytokines signal the central nervous system (CNS) are
unknown, but possibilities include: 1) the direct entry of cytokine into the
brain across the blood-brain barrier by a saturable transport mechanism: 2) the
interaction of cytokine with circumventricular organs such as the orgnum
vasculosum of the lamina terminalis [OVLT] and area postrema, which lack the
blood-brain barrier; and 3) activation of afferent neurons of the vagus nerve.
Increasing evidence has suggested that the afferent vagus nerve is an important
pathway for immune-to-brain communication. However, there are inconsistent
findings for the involvement of the afferent vagus nerve in the mediation of
transmitting inflammatory signals to the brain. Thus, we describe here the
functional relevance of the vagal afferent nerve in mediating these effects. An
understanding of the mechanisms involved in immune-to-brain communication
should permit us to create new drugs as therapeutic targets to decrease
sickness or promote recovery. This review focuses on recent discoveries of the
multipathway mechanisms for the induction of sickness behavior mediated through
neuroimmune interactions in the CNS.
[Back to top] IL-4
and IL-13: Their Pathological Roles in Allergic Diseases and their Potential in
Developing New Therapies
K. Izuhara, K. Arima and S.
Yasunaga
The incidence of allergic
diseases has dramatically increased in recent decades, and it is socially and
medically important to establish more useful strategies to overcome allergic
disorders. Various kinds of drugs are utilized for allergic patients; however,
some cases are unresponsive to these drugs and in others there are undesired
adverse effects. On the other hand, a substantial body of evidence has
accumulated pointing to the pivotal role of Th2-cytokines, interleukin (IL)-4,
and IL-13, in the pathogenesis of bronchial asthma. The evidence is categorized
as (1) expression of these cytokines in the bronchial lesions, (2) genetic
association of the signaling molecules of these cytokines, (3) analyses of
mouse models. In addition, the molecular mechanism of the signal transduction
of these cytokines has also been well characterized. Based on such information,
IL-4 and IL-13 have emerged as promising means of improving allergic states,
and several IL-4/IL-13 antagonists have been developed, among which soluble
IL-4 receptor is now in human trials. Identifying the structure of the IL-13
variant and of the IL-4/IL-13–inducing genes would be of great use. It is
expected that in the near future, several drugs will emerge based on these
strategies, which will give us wider choice in treating patients, depending on
the pathogenesis of the diseases.
[Back to top]
The
Use of Leukotriene Modifying Drugs in Asthma and Other Respiratory Diseases
J.A. Corless and M. Paracha
Only rarely in modern medicine is
an entirely new class of drug developed. Recently, a number of drugs that act
as leukotriene modifiers (LTM’s) have been licensed for use in the treatment of
asthma. Airway obstruction in asthma has two key components –
bronchoconstriction of airway smooth muscle and airway inflammation. Although a
number of mediators are involved in this process, it has been demonstrated that
leukotrienes can precipitate both. Leukotrienes are formed in eosinophils, mast
cells and neutrophils. LTM’s have been shown to attenuate bronchial
hyper-reactivity and reduce chemotaxis of inflammatory cells in the asthmatic
airway. This article reviews the data from clinical trials of LTM’s, discusses
their role in asthma therapy and postulates on use in other common respiratory
diseases.
[Back to top] A
Role for Leptin in the Systemic Inflammatory Response Syndrome (SIRS) and in
Immune Response
W. Waelput, P. Brouckaert, D.
Broekaert and J. Tavernier
Leptin was originally identified
as an adipocyte-derived cytokine with a key role in the regulation of the
energy balance. Subsequent research has, however, revealed that leptin’s
biological action is not restricted to its effects on appetite and food intake,
but rather has a much more pleiotropic character. Evidence is now accumulating
that it has important functions in reproduction, hematopoiesis, HPA-axis
endocrinology and angiogenesis. In this review, we have focused on the effects
of leptin in the immune system, which can be found in both the antigen-specific
immunity and in the inflammatory effector system.
[Back to top] Oxidative
Stress and Gene Transcription in Asthma and Chronic Obstructive Pulmonary Disease:
Antioxidant Therapeutic Targets
Irfan Rahman
Inflammatory lung diseases such
as asthma and Chronic Obstructive Pulmonary Disease (COPD) are characterised by
systemic and local chronic inflammation and oxidative stress. The sources of
the increased oxidative stress in patients with asthma and COPD derive from the
increased burden of inhaled oxidants, and from the increased amounts of
reactive oxygen species (ROS) generated by several inflammatory, immune and
structural cells of the airways. Increased levels of ROS produced in the
airways are reflected by increased markers of oxidative stress in the
airspaces, sputum, breath, lungs and blood in patients with asthma and COPD.
ROS, either directly or via the formation of lipid peroxidation products such
as acrolein, 4-hydroxy-2-nonenal and F2-isoprostanes, may play a role in
enhancing the inflammation through the activation of stress kinases (JNK, MAPK,
p38, phosphoinositide 3 (PI-3)-kinase/PI-3K-activated serine-threonine kinase
Akt) and redox sensitive transcription factors such as NF-kB and AP-1. Recent
data have also indicated that oxidative stress and pro-inflammatory mediators
can alter nuclear histone acetylation/deacetylation allowing access for
transcription factor DNA binding leading to enhanced pro-inflammatory gene
expression in various lung cells. Furthermore, oxidative stress may alter the
balance between gene expression of pro-inflammatory mediators and antioxidant
enzymes in favor of inflammatory mediators in the lung. Thus, the presence of
oxidative stress may have important consequences for the pathogenesis of asthma
and COPD. Identification of genes that predispose to the development of asthma
and COPD may identify novel therapeutic targets. Future work is directed to
understand the molecular mechanisms of antioxidants on ROS-mediated cell
signaling pathways and inhibition of inflammatory response that would provide
information for the development of novel antioxidant therapeutic targets in
asthma and COPD. Effective wide spectrum antioxidant therapy that has good
bioavailability and potency is urgently needed to control the localised
oxidative and inflammatory processes that occur in the pathogenesis of asthma
and COPD. In addition, development of such novel antioxidant compounds would be
therapeutically useful in monitoring the oxidative and inflammatory biomarkers
in the progression/severity of asthma and COPD.